Trans-prostaglandin-like compounds and methods

ABSTRACT

Trans-prostaglandin-like compounds wherein the chain attached to the C-3 carbon atom of the cyclopentane ring is of various lengths and the chain attached to the C-2 carbon atom of the cyclopentane ring contains a furan ring, a thiophene ring or sulfur.

United States Patent 1w:

Patterson et al.

TRANS-PROSTAGLANDIN-LIKE COMPOUNDS AND METHODS Inventors: John W.Patterson, Mountain View;

John H. Fried. Palo Alto. both of Calif.

Assignee: Synte x (U.S.A.) Inc.. Palo Alto v Calif.

Filed: Feb. 23, 1973 Appl. No.: 335,432

U.S. Cl. 260/347.3; 424/275; 424/285: 260/332.2 A: 260/3322 C: 260/3322R; 260/347.4. 260/468 D: 260/468 J; 260/5l4 D; 260/514 J Int.Cl.'......... C07D 307/34 Fleld of Search 260/3473. 347.4

[ Nov. 25, 1975 [56] Reierences Cited OTHER PUBLICATIONS Apsimon. TheTotal Synthesis of Natural Products. Vol. I. pp. l32-l34.Wiley-lntersciencc NY (1973).

Primary Examiner-John D. Randolph Attorney, Agent or Firm-Gerard A.Blaularh; William B. Walker 21 Claims. No Drawings 1 TRANS-PROSTAG LANDIN-LIKE COM POUN DS AND METHODS SUMMARY OF THE INVENTION Amongst thenovel (dl) mixtures of compounds, disomeric and l-isomeric compounds ofour invention are those represented by the formulas:

'/ (CH ClI on on (I) (II) wherein R is -H or CH,; m is a whole integerfrom zero through eight;

Ais

O l -cn D (cs co a BACKGROUND OF THE INVENTION l. The Invention Thisinvention relates to prostaglandin-Iike compounds.

More particularly, it relates to trans-prostaglandinlike compounds ofFormulas (l) and (II) above wherein the chain attached to the C-3 carbonatom ofthe cyclopentane ring is of various length and the chain attachedto the C-2 carbon atom of the cyclopentane ring contains a furan ring, athiophene ring or sulfur. The nomenclature used for the compounds ofFormulas (I) and (II) is discussed more fully below.

2. The Prior Art Prostaglandins have clasically been described aschemically related -carbon chair hydroxy fatty acids having the basicskeleton of prostanoie acid:

9 8,. e 4 I 2 coon IOOVV I 12 1 16\ ia\/2o Prostanoic Acid Theprostaglandins. as described immediately above. havinga hydroxy group atthe G] 1 position and a keto group at the C-9 position are known as thePOE series, those having a hydroxy! group in place of the keto group areknown as the PGF series and are further designated by an or or B suffixto indicate the configuration of the hydroxyl group at said position.The natural compounds are the a-hydroxy substituted compounds. They maycontain different degrees of unsaturation in the molecule, particularlyat C-5. C-l3 and 017. the unsaturation is also indicated by a suffix.Thus, for example, PGE refers to a prostanoic acid having a trans olefinbond at the l3-position. For a review on prostaglandins and thedefinition of primary prostaglandins. see, for example, S. Bergstrom,Recent Progress in Hormone Research. 22, pp. 153-175 (I966) and Science,I57. p. 382 (I967) by the same author.

Prostaglandins are widely distributed in mammalian tissues and have beenisolatedfrom natural sources in very small amounts. In addition, anumber of the natural occurring prostaglandins have been prepared bychemical synthesis; note, for example, J. Am. Chem. Soc., 91, p. 5675(I969), J. Am. Chem. Soc., 92, p. 2586 (I970) and J. Am. Chem. Soc., 93,pp. l489-l493 (I971) and references cited therein, W. P. Schneider etal., J. Am. Chem. Soc.. 90, p. 5895 (I968), U. Axen et al., Chem.Commun., p. 303

(I969), and W. P. Schneider, Chem. Commun., p. 304 (1969).

Because of the remarkable range of biological and pharmacologicalproperties exhibited by this family of compounds, a great deal ofinterest has focused upon such compounds and, accordingly, we havediscovered novel trans-prostaglandin-like compounds wherein the chainattached to the C-3 carbon atom of the cyclopentane ring is of variouslengths and the chain attached to the C-2 carbon atom of thecyclopentane ring contains a furan ring. a thiophene ring or sulfur.

FURTHER DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS Asdiscussed above, prostaglandins have for the most part classically beennamed using as the base for such nomenclature the 20-carbon chainhydroxy fatty acids having the basic skeleton of prostanoic acid. Forthe naturally occurring prostaglandis this nomenclature has sufficed.

However, in view of the lengthening and shortening of the side chains(and the increased complexity of the side chains) attached at the C-2and 03 carbon atoms of the cyclopentane nucleus. as well as othersubstituents attached to the cyclopentane nucleus. it is readilyapparent that a more systematic nomenclature must be pairs, i.e.. amixture of the d and I isomers, or the indiuscd. vidual d-isomers andl-isomers. Thus, the (dl) pairs are Therefore, in the description whichfollows. the coma mixture of the d and I isomers. For examp e. thepounds will be named as substituted cyclopentanes in pounds of For u arely a mixture Of which the cyclopentane nucleus will be numbered as 5follows:

0 R )g; A a 10. .(cu ctt Thus (dl)-PGF. having the structure H and itsmirror image, I 2 4 3 OH 1 (A) O B A would be systematically named(dl)-2a-(6-carboxy- (CH CH hex-l-yl)-3B-(3a-hydroxy-trans-l-octenyl)-4a-2 3 hydroxy-l-oxocyclopentane.

According to already established convention in the art. the chainattached to the C-3 carbon atom of the (I cyclopentane ring of naturallyoccurring prostaglandins 1 having a trans double bond nearest to saidC-3 carbon atom is depicted by structural configuration formula thuslyThe individual isomers are, of course, represented by Formulas (l) and(ll) individually.

@ To avoid undue prolixity, only one isomer. namely (CH CHthat-analogous to that depicted by Formula (I), rather W 2 4 3 thanFormula (A,). will be shown, it being understood that in thespecification and claims the mirror images 40 for the (dl) mixtures andthe individual d-isomers and l-isomers are also encompassed thereby.

It is to be further understood that encompassed (B) within thisinvention are racemic mixtures and diastereomeric mixtures. It is to beunderstood and will be apparent to those The novel compounds of ourinvention and novel skilled in the art that the compounds of Formulas(l) processes for their production are illustratively repreand (II)above and (I) through (7) below exist as (dl) sented by the followingreaction sequence:

OAc O R R Chi (CH CH (1) OS1(CH3)2C (CH3) 3 (CH CH osi. (CH3) c (CH3) 3(CH en OH 3 R 5 (CH Ci-I In the above flow shcct Formula (4) is acomposite of 0 2 Formulas (4'). (4') and (4'); and N CO R R is -H or--CH,; 65

m is a whole integer from zero through eight; S I Ac is acetyl; 2 A is 2H CO R or p is a whole integer from one through six; A is in which R andp are defined as above; A is in which R and p are defined as above; A is--CH,S(O).(CH|),CO|R' in which q is a whole integer from zero throughtwo; and

in which R, n, q and p are defined as above; and the wavy linerepresents the aor B- configuration or mixtures thereof; and in Steps(d) [(4) (4')] and (e) [(4) (4')] A is --CH,S(CH,),CO,R (in which R andp are defined as above) only.

The term "alityl of from one through ten carbon atoms" includes bothstraight and branched chain alkyl groups; and the dotted line Irepresents the a-configuration.

The reaction steps and definitions given above represent an overall viewof the methods used for the preparation of the novel compounds of thisinvention. For a more detailed explanation of the reaction stepreference can be made to the examples themselves and the formulas anddefinitions preceding each of the examples.

in carrying out the processes of our invention, the compounds of Formula(I) are, according to step (a), reacted with a freshly preparedcopper(l) lithium reagent of Formula 2 (defined more fully in Example iat a temperature of l00 to 20C, preferably -90 to 0C. in ether (diethylether), methyl ethyl ether, and the like, for from 5 minutes to 24hours. preferably from ten minutes to one hour; .followed by theaddition of acetic anhydride and maintaining a temperature of -60 to20C, preferably -40 to r-25C. for from 5 to 60 minutes to yield thecompounds of Formula (2) which are then removed from the reactionmixture according to methods known in the art.

The compounds of Formula (2) are, according to step (b). treated withlithium at a temperature of -90 to -33C, preferably -80 to 60C, for from5 to 30 minutes, followed by treatment with trimethylborate at atemperature of to .*-50C, for from l0 to 50 minutes, and the addition ofchloro compounds of Formula A (defined more fully in Example 2) at atemperature of 70 to 40C, preferably -60 to 50C, for from l0 to 60minutes, to yield the compounds of For mula (3). The conversion of thecompounds of Formula (2) to Formula (3) can be carried out in a varietyof suitable inert organic solvents, e.g., tetrahydrofuran, l,2-dimethoxyethane, diglyme, dioxane, preferably tetrahydrofuran, or mixturesthereof.

The compounds of Formula (3) are. according to step (c), treated undermild acidic conditions with an acid, for example, acetic,dichloroacetic, and the like. preferably acetic acid, at a temperatureof ID to 50C, preferably 20 to 30C, for from 10 to 30 hours, preferablyl2 to 18 hours. to yield the compounds of Formula (4). Advantageously,this reaction is carried out in the presence of an inert organicsolvent, e.g.. tetrahydrofuran, dioxane, methanol, and the like,preferably tetrahydrofuran. The isomeric mixtures obtained are separatedby column or thin-layer chromatography.

The compounds of Formula (4), wherein A is CH,S(CH,),CO,R only. are,according to step (d), oxidized with one molar equivalent of sodiummetaperiodate per mole of compound of Formula (4) to obtain thecompounds of Formula (4). Using two molar equivalents of sodiummetaperiodate per mole of compounds of Formula (4), wherein A is-CH,S(CH,)- ,CO,R only, according to step (e), there is obtained thecompounds of Formula (4). The conversion of the compounds of Fonnula (4)to the compounds of Formulas (4) and (4) is carried out in dioxane,aqueous alcohols and the like, preferably aqueous methanol.

The compounds of Formula (4), i.e., the compounds embraced by Formulas(4'), (4) and (4) are, according to step (f) treated with a reducingagent to convert the l-oxocyclopentanes to the l-hydroxycyclopentanes ofFormula (5). Suitable reducing agents are sodium borohydride. zincborohydride. and the like, preferably sodium borohydrlde. and thereaction is carried out in methanol, ethanol, propanol. and the like.preferably methanol. The temperature for this step can vary from l0 to25C, however, an initial temperature of 0C is preferred. Thethus-obtained compounds of Formula (5) are then separated by column orthin-layer chrom atography.

The thus-obtained compounds of Formulas (4) and (5) are hydrolyzedaccording to step (g). to obtain their corresponding free acids ofFormulas (6) and (7). The ester hydrolysis reaction is carried outbiologically, preferably enzymatically, using a pancreatic lipasepreparation to cleave the ester group, thus yielding the free acids. Thecarboxylic acids are purified by column or thin-layer chromatography.

it is to be understood that any of the isomeric mixtures obtained can beseparated and/or purified by any suitable separation and/or purificationprocedure. such as. for exam ple, extraction. filtration. distillation.evaporation. crystallization. column chromatography, thinlayerchromatography. and the like. Specific illustrations of typicalseparation and/or purification procedures can be had by reference to thepreparations and examples described herein below. Other equivalentseparation and/or purification procedures could. of course. also beused.

However. as described above it is preferred to separate the isomericmixtures at a relatively early stage, i.e.. following the conversion ofthe compounds of Formula (3) to (4). step (c). and also subsequent tothe conversion of the compounds of Formula (4) to Formula (5). step (f).

As noted above. the compounds of Formulas (l) and (ii). wherein R is H.can also be administered in the form of their pharmaceuticallyacceptable salts. i.e.. salts which do not significantly adverselyaffect the pharmaceutical properties of the parent compounds. Suitablepharmaceutically acceptable salts include. for example. the salts ofsodium. potassium. aluminur calcium. iron, magnesium. ammonia. maieate.benz ate. acetate and the like. The salts can be prepared according toconventional procedures and. for example. can be conveniently preparedby treating the corresponding free acids with about one molar equivalentof a pharmaceutically acceptable base per molar equivalent of free acid.Suitable pharmaceutically acceptable bases include. for example, sodiumhydroxide, potassium hydroxide, sodium carbonate. potassium carbonate.sodium bicarbonate. ammonium hydroxide. calcium hydroxide,trimethylamine. triethylamine. tripropylamine.fi-(dimethylamino)ethanol. B-(diethylamino)ethanol. arginine, lysine.caffeine. procaine and the like. Typically the reaction is conducted inan aqueous solution, alone or in combination with an inert, watermiscible organic solvent, at a temperature of are also useful incontrolling or palliating hypertension in mammals and further exhibitcentral nervous system depressant activity. in mammals. and are usefulas sedatives. in addition. the compounds are useful for inducing labor.in pregnancy. and for inducing menses to correct or reduce menstrualabnormalities. The compounds also possess anti-fertility properties. Inaddition. they exhibit anti-inflammatory activities and are thus usefulas anti-inflammatory agents.

These compounds can be administered in a wide variety of dosage forms.either alone or in combination with other phsnnaceutically compatiblemedicaments. in the form of pharmaceutical compositions suited for oralor parenteral administration or inhalation in the case ofbronchodilators. The compounds are typically administered aspharmaceutical compositions consisting essentially ofthc compoundsand/or salts. of the invention, and a pharmaceutical carrier. Thepharmaceutical carrier can be either a solid material. liquid. oraerosol. in which the compound and/or salt is dissolved. dispersed orsuspended. and can optionally contain small amounts of preservativesand/or pH-buffcring agents. Suitable preservatives which can be usedinclude. for example. benzyl alcohol and the like. Suitable bufferingagents include. for example. sodium neetate and pharmaceutical phosphatesalts and the like.

The liquid compositions can. for example. be in the form of solutions.emulsions. suspension. syrups. or elixirs. The solid compositions cantake the form oftablets. powders. capsules. pills or the like.preferably in unit dosage forms for simple administration or precisedosages. Suitable solid carriers include, for example. pharmaceuticalgrades of starch. lactose. sodium saccharin. talcum. sodium bisulfiteand the like.

For inhalation administration. the compounds can. for example. beadministered as an aerosol comprising the compounds or salts in an inertpropellant together with a cosolvent (e.g.. ethanol) together withoptional preservatives and buffering agents. Additional generalinformation concerning the inhalation administration of aerosols can behad by reference to U.S. Pat. Nos. 2.969.691 and 3.095.355.

The compounds are typically administered in dosages of about from 0.1 to10 mg. per kg. of body weight. The precise effective dosage will. ofcourse. vary depending upon the mode of administration, condition beingtreated, and host.

A further understanding of the invention can be had from the followingnon-limiting preparations and examples. Also. where necessary.preparations and examples are repeated to provide starting materials forsubsequent preparations and examples. The term ambient or roomtemperature refers to about 20C.

The symbol (t) appearing above the double bond in the formulas shown inPreparation 1 and Example l denotes the trans configuration.

Preparation l [Q],Cu(l)Li wherein [Q] is in which m is a whole integerfrom zero through eight; and

the wavy line l represents the aor B-configurations or mixtures thereof.

A. A solution of 210 ml. of hexanoyl chloride in 750 ml. of carbontetrachloride is cooled in an ice bath. 200 G. of aluminum chloride isadded over a 30 minute period. while acetylene is bubbled through thesolution. After 30 minutes. the ice bath is removed and the acetyleneaddition is continued for six hours. The reaction mixture is poured onto56 kg. of ice. extracted twice with 500 ml. of methylene chloride andthe combined organic layers washed successively with 500 ml. of waterand 500 ml. of saturated sodium bicarbonate. The solution is then driedover sodium sulfate. concentrated in vacuo. followed by distillation toyield trans-lchlorooct-l-en-S-one.

a. Similarly. substituting other alkanoyl chlorides for example.

butanoyl chloride. octanoyl chloride. or decanoyl chloride,

for hexanoyl chloride. in the procedure of Preparation HA). isproductive of the Corresponding trans-lchloroalk-l-en-Lone. for example.

transl -chlorohexi -en-3 on e. trans-l-chlorodec-i-en-3-one. and transl-chlorododec l -e n-3- one.'

(B) A mixture containing l9 gJoftrans-l -chloroocttransl -chlorohexl-en-3-one. trans-l -chlorodecl -en-3-one, or transl -chlorododecl -en-3one,

for trans-l-chlorooct l-en-3-one. in the procedureof Preparation 1(8),is productive of the corresponding trans-l-iodoalk l-en-li ones. forexample.

trans-'1-iodohex-l-en-3-one. trans-l-iododec-l -en-3-one, and transl-iodododeci -en-3-one.

C. The residue consisting oftrans-l-iodooct-l-en- 3-one. obtained inPreparation -l(B). is then dissolved in 150 ml. of diethyl ether andslowly added over a 30 minute period to a suspension containing 2.5 g.of lithium aluminum hydride in 200 ml. of diethyl ether, and theresulting'mixture is stirred at room temperature under nitrogen for 12hours. The reaction mixture is then worked up by the sequential dropwiseaddition of 3 ml. of water. 3 ml. of 15% aqueous sodium hydroxide and 9ml. of water. The mixture is then filtered and the resulting filteredcake is washed with t'wo 50 ml. portions of diethyl ether. The combinedfiltrate and diethyl ether washings-- are dried overpotassium-"carbonate. then filtered. and the resulting filtrateevaporated to yield a residue of (dl)-trans-l iodooct-l-en-3-ol.

a. Similarly, substituting other trans-l-iodo-allt-l-en- 3-ones, forexample,

trans-l-iodohexl-en-3one, v transl -iododec l en-3-one, and transi-iodododecl -en-3-one.-

for transl -iodooct-l -en-3 -one. 1 in I the procedure of PreparationNC). is productive of the corresponding dl)-trans-l-iodoallt l-en-5-ols.for example.

(dl)-trans-l-iodohex-i-en-3-ol. I (dl)-trans-l-iododec-l-en-3-ol. and(dl)-transl iodod'odec-l '-en-3-ol.

D. A mixture of 26.2 g. of (dl)-trans-l-iodooct-l-cn- 3-ol. l4.8 g. ofphthalic anhydride and ml. of pyridine are heated at 50C for six hours.The resulting solution is poured into 200 ml. of ice-cold 6Nhydrochloric acid'and extracted four times with lOO ml. of ether. Theethereal solution is extracted with 300 ml. of icecold two percentsodium hydroxide. The aqueous solution is washed once with 300 ml. ofether. then acidified with dilute hydrochloric acid and extracted fourtimes with I00 ml. of ether. The ethereal solution is concentrated atreduced pressure to give 20.5 g. of phthalate half ester. This ester isdissolved in 100 ml. of methylene chloride. cooled on an ice bath andtreated with a solution of 6 g. of (--)-a-phenethylamine in 50 ml. ofmethylene chloride. The methylene chloride is evaporated in vacuo andthe resulting amine salt is recrystallized repeatedly from acetonitrile.The thusobtained amine salt is hydrolyzed with I00 ml. of l5% sodiumhydroxide in methanol at room temperature for 12 hours. The reactionmixture is diluted with 500 ml. of waterand extracted twice with 300 ml.of ether. The ethereal solution is washed with five percent hydrochloricacid. dried over anhydrous sodium sulfate. and the ether removed invacuo. The residue is then chromatog raphed on 200 g. of silica gelusing ether-hexane. and those fractions eluted with 10 to 12%ether-hexane yield 3 g. of 3-(S)-trans-l-iodooct-l-en-3-ol.

a.. Similarly. substituting other (dl)-trans-l-iodoalkl-en-3-ols, forexample, i

( dl)- trans i -iodohex-i -en-3-ol. (dl)- trans-l-iododec-l -en-3-ol,and (dl)-transl -iodododec-l -en-3-ol,

for (dl)-trans-l-iodooct l-en-3-ol. in the procedure of Preparationl(D), is productive of the corresponding3-(S)-trans-l-iodoalk-l-en-3-o|s. for example,

3-(S)-trans-l iodohex-l-en-li-ol, 3(S)-trans-l-iododec-l-en-Zl-ol. and3-( S )-transl -iodododecl -en3-ol.

E. A mixture of 26.2 g. of (dl)-trans-l-iodooct-l-en- 3-ols, 14.8 g. ofphthalic anhydride and 100 ml. of pyridine are heated at 50C. for sixhours. The resulting solution is poured into 200 ml. of ice-cold 6Nhydrochloric acid and extracted four times with lOO ml. of ether. Theethereal solution is extracted with 300 ml. of icecold two percentsodium hydroxide. The aqueous solution is washed once with 300 ml. ofether. then aciditied with dilute hydrochloric acid and extracted fourtimes with 100 ml. of ether. The ethereal solution is concentrated atreduced pressure to give 20.5 g. of

sodium hydroxide in methanol at room temperature for l2 hours. Thereaction mixture is diluted with'300 ml. of ether. The ethereal solutionis washed with five percent hydrochlorlc acid. dried over anhydroussodium sulfate. and the ether removed in vacuo. The residue is thenchromatographed on 200 g. of silica gelusing ether-hexane.and thosefractions eluted with 10 to l2% ether-hexane yield 3 g. of3-(R)-trans-l-iodo-octl-en-3-ol.

a. Similarly, substituting other (dl)-trans-l-iodoalkl-en-3-ols, forexample.

(dl )-trans-l -iodohex-l-en-3-ols. (dl )-transl -iododecl -en-3-ols. and(dl )-transl -iodododecl -en-3-ols,

for (dl)-trans-l-iodooet-l-en- L], in the procedure of Preparation HE).is productive of the corresponding 3-(R)-trttns-l-lodoalk-l-en-3-ols.for example.

3-( R )-transl -iodohexl -en-3-ol, 3-(R )-transl -iododecl -en-3-ol. and3-( R )-transl -iodododec-l -ert-3-ol.

F. To a solution of 300 g. of (dl)-trans-l-iodooct-len-3-ol. obtained inPreparation l(C), and 25 g. of imidazole in 50 ml. ofN,N-dimethyltormamide is added 18.5 g. of t-butyldimethylchlorosilaneand the resulting reaction mixture is stirred under a nitrogenatmosphere for one hour at room temperature. The reaction mixture isthen poured into 300 ml. of ether and 200 g. of ice. The etherealsolution is separated and washed twice with 200 ml. of water and 100 ml.of saturated sodium bicarbonate. After drying over sodium sulfate, theethereal solution is concentrated in vacuo, followed by distillation toyield (dl)-trans-l-iodo-3-t-butyldimethylsiloxyoct-l-ene.

a. Similarly, substituting other (dl)-trans-l-iodoalkl-en-3-ols,prepared in Preparation l(C)(a), for example,

(dl)-trans-l -iodohexl -en-3-ol, (dl)-trans-l-iododec-l-en-3-ol, and(dl)-transl -iodododecl -en-3-ol.

for (dl)-trans-l-iodooct-l-en 3-ol, in the procedure of Preparation HP),is productive of the corresponding dl )-transl-iodo-3-t-butyldimethylsiloxyalkl -enes,

for example,

(dl)-trans-l -iodo-3-t-butyldimethylsiloxyhexl -ene,

( dl )-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

(dl )-transl -iod0-3-t-butyldimethylsiloxydodecl -ene.

b. Similarly, substituting the 3-(S)-trans-l-iodoalk-l- 14 c. Similarly,substituting the 3-(R )-transl -iodoalkl en-3-ols, obtained inPreparation HE) and l(E)(a). for example.

3-( R )-transl -iodooetl en-3-ol. 3-(R)-transl -iodohexl -en-3-ol,3-(R)-trans-l-iododec--en-3-ol. and 3-( R )-transl -iodododecl -en-3-ol.

for (dl)-trans-l-iodooct-l-en-3-ol in the procedure of Preparation l(F)is productive of the corresponding3-(R)-truns-l-iodo-3-t-butyldimethylsiloxyulk-I-enes. for example,

3-( R )-transl -iodo-3-t-butyldimethylsiloxyoctl -ene,

3-(R )-transl -iodo-3-t-butyldimethylsiloxyhexl -cnc,

3-(R)-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

3-(R )-transl -iodo-3-t-butyldimethylsiloxydodecl-ene.

G. 15 Ml. ofa l.5 M n-butyl lithium in hexane solution is admixed to amixture containing 7.36 g. of (dl)t-rans-l-iodo-3-t-butyldimethylsiloxyoetl -enes, prepared in Preparationl(F), in 8 ml. of hexane at 78C. under an argon atmosphere. Theresulting mixture is stirred and maintained at -78C., under argon, for30 minutes. During this time a second mixture containing 4.4 g. ofbistrimethylphosphite copper(l) iodide in 60 ml. of diethyl ether isprepared and maintained under argon and cooled to i78C. At the end ofthe 30 min utes period, previously referred to, the first mixture isadmixed to the second mixture and the temperature of the resultingmixture is brought to -50C. The formation of the (dl) copper(l) lithiumreagent having the octene moiety is periodically monitored by a Gilmantest [notez Gilman and Sculze,J. Am. Chem. Soc, v. 47,

en-3-ols, obtained in Preparation 1(0) and l(D)(a),

for example,

3-( S )-transl -iodooctl -en-3-ol,

3-( S )-transl -iodohex-l -en-3-ol, 3-(S)-trans-l-iododec-l-en-3-ol, and3-(S )-transl -iodododeel -en-3-ol,

3-( S )-transl -iod0-3-t-butyldimethylsiloxyoetl -ene, 3 S )-transl-iodo-3-t-butyldimethylsiloyxhexl -ene, 3-( S )-transl-iodo-3-t-butyldimethylsiloxydecl -ene, 3-( S )-transl-iodo-3-t-butyldimethylsiloxydodecl -ene 2002 (l925)], and maintained at50C. until a negative Gilman test is obtained (about 45 minutes).

a. Similarly, substituting other(dl)-trans-l-iodo-3-tbutyldimethylsiloxyalk-l-enes, prepared inPreparation .1(F)(a), for example,

(dl)-trans-l-iodo-3-t-butyldimethylsiloxyhex-l -ene,

(dl)-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

(dl)-transl -iodo-3-t-butyldimethylsiloxydodecl -ene,

for (dl)-trans-l-iodo-3-t-butyldimethylsiloxyoct-l-ene in the procedureof Preparation l(G) is productive of (dl) copper(l) lithium reagentshaving the respective alkene moieties, for example, hexene, decene anddodecene.

b. Similarly, substituting the3-(S)-trans-l-iodo-3-tbutyldimethylsiloxyalk-l-enes, obtained inPreparation l(F)(b), for example,

3-(S)-transl -i0do-3-t-butyldimethylsiloxyocz:- l -ene.

3-(S)-transl -iodo-3-t-butyldimethylsiloxyhexl -ene,

3-(S)-transl -iodo-3-t-butyldimethylsiloxydecl -ene,

and

3-(S)-transl -iodo-3-t-butyldimethy lsiloxydodecl-ene,

for (dl)-trans-l -iodo-3-t-butyldimethylsiloxyoctl -enes in theprocedure of Preparation H6) is productive of 3-(S) copper(l) lithiumreagents having the respective 15 alkenc moieties, for example, octene,hexene, decene and dodecene.

c. Similarly, substituting the3-(R)-trans-l-iodo-3-tbutyldimethylsiloxyallt-l-enes, obtained inPreparation 1(F)(e), for example,

3 R )-transi -iodo-3-t-butyldimethylsiloxyoetl -ene, 3 R )-transl-iodo3-t-butyldimethylsiloxyhex-i -ene,

3 R )-trans-l -iodo-3-t-butyldimethylsiloxydecl-ene, and 3 R )-trans i-iodo-3-t-butyldimethylsiloxydodecl -ene,

i or (dl )-transl -iodo-3-3-t-butyldimethylsiloxyoctl-enes in theprocedure of Example 1(0) is productive of 3-(R) copper(l) lithiumreagents having the respective alkene moieties, for example, octene,hexene, decone and dodecene Preparation 2 ClCH 2 2 U C R wherein R isalkyl of from one through ten carbon atoms; and

n is a whole integer from zero through four.

A. 11.2 G. of 3-(fur-2-yl)propanoic acid is added, with stirring, to 93ml. of a solution of tetramethylammonium hydroxide. The water is thenevaporated under reduced pressure from the resulting solution to give asemi-solid residue which is then suspended in 75 ml. of anhydrousN,N-dimethylformamide and stirred vigorously while 9.0 ml. of methyliodide is added over a five minute period. The reaction mixture isstirred overnight and poured into 300 ml. of water. The thusobtainedaqueous solution is extracted with four 100 ml. portions of ether. Theether extracts are combined and washed successively with 200 ml. ofwater and 200 ml. of saturated sodium chloride, and dried over anhydroussodium carbonate. The ether is removed in vacuo and the thus-producedoil distilled to yield 13.37 g. of 45 methyl 3-(fur-2-yl)propanoate.

a. Similarly, substituting 2-furoic acid, 2-(fur-2-yl)acetie acid.4-(fur-2-yl)butanolc acid, and 5-(fur-2-yl)pentanoic acid,

for 3-(fur-2-yl)propanoic acid, in the procedure of Preparation 2(A), isproductive of methyl (fur-Z-ylJcarboxylate,

methyl 2-(fur-2-yl)scetate,

methyl 4-(fur-2-yl)butanoate, and

methyl 5-(fur-2-yl)pentanoate, respectively.

B. 3.68 Ml. of N,N-dimethylformamide is cooled on an ice bath andtreated with 4.6 ml. of phosphorous oxychloride. The resulting solutionis stirred at 5C for 20 minutes under a nitrogen atmosphere. 7.3 G.oi'methyl 3-(fur-2-yl)propanoate is then added and the resultingsolution is stirred for one hour at 5C and then for two hours at roomtemperature. The reaction mixture is poured onto 200 g. of ice, 4 g. ofpotassium carbonate is added and the resulting solution is thenextracted twice with l00 ml. of ether. The combined ethereal solutionsare dried over anhydrous sodium sulfate and the solvents removed invacuo to yield 4.7l g. of methyl 3- (5-formyliur-2-yl)propanoate.

a. Similarly, substituting methyl (fur-2-yl)carboxylate, methyl2-(fur-2-yl)acetate, methyl 4-(fur-2-yl)butanoate, and methylS-(fur-Z-yDpentanoate,

for methyl 3-(fur-2-yl)propanoate, in the procedure of Preparation 2(8),is productive of methyl (S-formylfur-Z-yl)carboxylate,

methyl 2-(5-formylfur-2-yl)acetate,

methyl 4-(5-formylfur-2-yl)butanoate, and

methyl 5-(5-formylfur-2-yl)pentanoate, respectively.

b. In like manner, substitution of other alkanotes of the w-(fur-Z-yl)compounds, prepared in Preparation 2(A) (b), in the procedure ofPreparation 2(8) is productive of the corresponding alkyl esters havingfrom two to ten carbon atoms, e.g. ethyl, propyl, isopropyl. octyl, andthe like, of the respective w-(S-formylfur- 2-yl) compounds.

C. A solution of 4.l0 g. methyl 3-(5-formylfur-2- yl)propanoate in 25ml. of methanol is cooled on an ice bath and treated with 258 mg. ofsodium borohydride. After ten minutes the solution is poured into icewater and extracted twice with ml. of ether. The combined ethereallayers are dried over sodium sulfate and concehtrated in vacuo to yield3.08 g. of methyl 3-(5- hydroxymethylfur-2-yl)propanoate.

a. Similarly, substituting methyl (5-formylfur-2-yl)carboxylate, methyl2-(5-fonnylfur-2-yl)acetate, methyl 4-(S-formylfur-2-yl)butanoate, andmethyl 5-(5-forrnylfur-2-yl)pentanoate,

for methyl B-(S-t'ormylfur-Z-yl)propanoate, in the procedure ofPreparation 2(C), is productive of methyl(5-hydroxymethylfur-2-yl)carboxylate,

methyl 2-(S-hydroxymethylfur-Z-yl)acetate,

methyl 4-(S-hydroxymethylfur-Z-yl)butanoate, and

methyl 5-(5-hydroxymethylfur-2-yl)pentanoate,

spectively.

b. In like manner, substitution of other alltyl esters of thew-(5-formylfur-2-yl) compounds, prepared in Prep- 17 ride and 2.75 g. oftriphenylphosphene in i ml. of N,N-dimethylformamide is stirred at roomtemperature for three hours. The N,N-dimethylformamide is then removedin vacuo and the resulting residue chromatographed on 200 g. of silicagel, eluting with ether-hexane. Those fractions eluted with l0%ether-hexane are combined and the solvent evaporated to yield methyl3-(5-chloromethylfur-2-yl)propanoate. -thiaalka. Similarly, substitutingmethyl (-hydroxymethylfur-2-yl)carboxylate,

methyl 2-(5-hydroxymethylfur-2-yl)acetate,

methyl 4-(S-hydroxymethylfur-Z-yl)butanoate, and

and

methyl 5-(S-hydroxymethyifur-Z-yl)pentanoate.

for methyl 3-(S-hydroxymethylfur-Z-yl)propanoate, in the procedure ofPreparation 2(D), is productive of methyl(S-chloromethylfur-Z-yl)carboxylate,

methyl 2-(S-chloromethylfur-Z-yl)acetate.

methyl 4-(S-chloromethylfur-Z-yl)butanoate, and

methyl $-(5-chloromethylfur-2-yl)pentanoate, respectively.

b. in like manner, substitution of other alkyl esters of them-(5-hydroxymethylfur-2-yl) compounds, prepared in Preparation 2(C) (b),in the procedure of Preparation 2(D) is productive of the correspondingalkyl esters having from two to ten carbon atoms, e.g. ethyl, propyl,isopropyl, octyl, and the like, of the respectivece-($-chloromethyifur-2-yl) compounds.

Preparation 3 2 clca OM1 co a wherein three 100 ml. portions of ether.The ether extracts are combined and washed successively with 300 ml. ofwater and 300 ml. of saturated sodium chloride and dried over anhydroussodium carbonate. The ether is removed in vacuo and the resulting oildistilled to yield 13.24 g. of methyl 3-(thien-2-yl)propanoate.

a. Similarly, substituting 2-thiophene carboxylic acid.2-(thien-2-yl)acetic acid, 4-(thien-2-yi)butanoic acid. and5-(thien-2-yl)pentanoic acid,

for 3-(thien-2-yl)propanoic acid, in the procedure of Preparation 3(A),is productive of 18 methyl (thien-2-yl)carboxylate, methyl2-(thien-2-yl)acetate, methyl 4-(thien-2-yl)butanoate. and methylS-(thien-Z-yl)pentanoate.

b. in like manner, substitution of other alkyl iodides for methyliodide, and using the appropriate starting acid [of Preparation 3, parts(A) and (A) (a)] in the procedure of Preparation 3( A) is productive ofthe corresponding alkyl esters having from two to ten carbon atoms, e.g.ethyl, propyl, isopropyl, octyl, and the like, of the respectiveai-(thien-2-yl) compounds.

B. I g. of methyl 3-(thien-2-yl)propanoate and 50 ml. of concentratedhydrochloric acid are placed in a 600 ml. beaker andcooled to -l0C in adry-ice/acetone bath. A stream ofhydrogen chloride gas is passed intothe reaction mixture with vigorous stirring and when the temperaturereaches 0C, l25 ml. of 37% formaldehyde is added at rate such that thetemperature remains below 5C. After the addition of the formaldehyde,the rcaction mixture is extracted with three 200 ml. portions of ether.The ether extracts are combined, washed successively with 200 ml. ofwater, 200 ml. of saturated sodium bicarbonate and dried over anhydroussodium sulfate. The ether is evaporated under reduced pressure and theresidue remaining is distilled to give 42 g. of methyl3-(S-chloromethylthien-Z- yl)propanoate.

a. Similarly, substituting methyl (thien-2-yi)carboxylate, methyl2-(thien-2-yl)acetate, methyl 4-(thien-2-yl)butanoate, and methyl5-(thicn-2-yl)pentanoate,

for methyl 3-(thien-2-yl)propanoate, in the procedure of Preparation3(8), is productive of methyl (5-chloromethylthien-2-yl)carboxylate,methyl 2-(S-chloromethyithien-Z-yl)acetate, methyl4-(5-chloromethylthien-2-yl)butanoate, and methyl5-(5-chloromethylthien-2-yl)pentanoate.

b. in like manner, substitution of other alkyl esters of the(thien-Z-yl) compounds, prepared in Preparation 3(A) (b), in theprocedure of Preparation 3(8) is productive of the corresponding alkylesters having from two to ten carbon atoms, e.g. ethyl propyl,isopropyl, octyl and the like, of the respectivem-(S-chloromethylthien-Z-yl) compounds.

Preparation 4 CICH,S(CH,),CO,R' wherein R, is alkyl of from one throughten carbon atoms; and

p is a whole integer of one through six.

(A) A mixture of I00 ml. of methanol, l25 ml. of chloroform, 10 drops ofconcentrated sulfuric acid and i0 g. of 4,4'-dithiadibutanoic acid isheated on an oil bath while lOO ml. of chloroform-methanol-waterazeotrope is allowed to distill out over a 2 hour period. The reactionmixture is cooled to room temperature, washed with ml. of saturatedsodium bicarbonate, dried over sodium sulfate and concentrated, followedby distillation at reduced pressure to yield dimethyl4,4'-dithiadibutanoate.

a. Similarly, substituting 2.2'-dithiadiacene acid.3.3'-tlithiadipropionie acid, 5.5'-dithiadipentanoie acid.6,6'-dithiadihexanoic acid. and 7,7-dithiadiheptanoic acid. for4.4'-dithiadibutanoic acid, in the procedure of Preparation 4(A). isproductive of. dimethyl 2,2'-dithiadiacetatc. dimethyl3.3'-dithiadipropunoate, dimethyl 5.5'-dithiadipentanoate. dimethyl6,6'-dithiadihexanoate. and dimethyl 7.7'-dithiadiheptanoate.

b. In like manner. substitution of other alkanols for methanol, andusing the appropriate starting acid [of Preparation 4. parts (A) and (A)(a)] in the procedure of Preparation 4(A) is productive of thecorresponding dialkyl esters having from two to ten carbon atoms. e.g..ethyl, propyl, isopropyl. octyl, and the like. of the respectivew,w'-dithiodialkanoates.

B. A solution of 26.7 g. of dimethyl 4,4- dithiadibutanoate. prepared inPreparr." 4(A). in ml. of dry carbon tetrachloride is cooled to 35C andtreated with 7.l g. of chlorine. The reaction mixture is stirred at -35Cfor 30 minutes to yield an orange solution of methyl4-ehlorosulfenylbutanoate, which is maintained at -35C, while a solutionof approximately 0.1 1 moles of diazomethane in 200 ml. of dry ether isadded. The reaction mixture is then allowed to warm to room temperaturefor 30 minutes and the solvent removed in vacuo. The resulting residueis distilled at reduced pressure to yield methyl6-chloro-5-thiahexanoate.

a. Similarly, substituting, dimethyl 2,2'-dithiadiaeetate,, dimethyl3,3'-dithiadipropanoate, dimethyl 5,5dithiadipentanoate, dimethyl6,6'-dithiadihexanoate, and dimethyl 7,7-dithiadiheptanoate.

for dimethyl 4.4'-dithiadibut'anoate. in the procedure of Preparation4(8), is productive of.

methyl 4-ehloro-3-thiabutanoate. methyl 5-chloro-4-thiapentanoate,methyl 7-ehloro--thiaheptanoate. methyl 8-chloro-7-thiaoctanoate, andmethyl 9-chlero-8-thianonanoate.

b. In like manner, substitution of other dialkyl esters of thew,w'-dithladialltanoatc compounds, prepared in Preparation 4(A) (b) inthe procedure of Preparation 4(8) is productive of the correspondingalkyl esters having from two to ten carbonatoms, e.g.. ethyl, propyl.isopropyl, oetyl. and the like. of the respectiveai-thiachloroalkanoates.

Preparation 5 This preparation illustrates methods of preparing apancreatic lipase preparation which can be used to cleave ester groupsfrom carboalkoxy cyclopentanes. In this preparation, l0 g. of crudepancreatic lipase lnote: Bioehem. Biophysics Aclm, v. 23, p. 264 l957)]is suspended in 65 ml. of water at 0C. The suspension is stirred for onehour at 0C. and then centrifuged for 20 minutes at 10,000 X g. Thesupernatant liquid is separated and maintained at 0C. for later use. Theprecipitate is again suspended in 65 ml. of water at 0C. and centrifugedas before. The supernatant liquid is separated and combined with thepreviously obtained supernatant liquid and then added to l30 ml. ofsaturated aqueous ammonium sulfate solution at 0C.. with stirring, andthen allowed to stand for five minutes. The resulting mixture is thencentrifuged at 10,000 X g. for 20 minutes. The supernatant liquid isdecanted and the precipitate is collected, then dissolved in sufficientwater to yield I25 ml. of solution. 15 ml. of saturated aqueous ammoniumsulfate solution is then added to the water solution yielding asuspension which is then centrifuged at 10,000 X g. for 20 minutes. Thesupernatant liquid is collected and treated with l00 ml. of saturatedammonium sulfate affording a second suspension, which is divided intotwo equal portions. Each portion is again centrifuged for 20 minutes atl0,000 X g., and in each instance the supernatant liquid is discarded(decantation) and the precipitate collected. Each pre cipitate is storedat 40C. prior to use.

The pancreatic lipase ester cleaving preparation is then preparedimmediately prior to use by dissolving one of the above precipitates in25 ml. of an aqueous 0.lM sodium chloride solution and 0.05M calciumchloride solution and then adjusting the pH to 7.2 by the carefuladdition (i.e., titration) of a 0.1M aqueous sodium hydroxide solution.

EXAMPLE I Step (a) OAC / (CH CH 0Si(CH ctcn i 3 wherein R isH or CH,; 2is [Q], Cu(l) Li in which [0] is (i) CH-CHCH(CHs)-CHs OSl(CHsls (CH,),

m is a whole integer from zero through eight; Ac is acetyl; and

the wavy line l represents the aor B-configuradodecenyl)-l-acetoxycyclopent-l-encs.

tron or mixtures thereof; D. Likewise. substituting2-methyleyclopent-2-en- A. l Mmoles of freshly prepared (dl) octentcopl-one. for cyclopent-Z-en-l-one. in the procedure of per(l) lithiumreagent [Preparation l(G)] is cooled to Example HA). is productive of(dl)-SB-(3a-and Bfl-t- 78C and treated with 0.82g. ofcyclopent-Z-en-l-one 5 butyldimethylsiloxy-trans-l-octenyl)-2-mcthyll in5 ml. of ether. After l5 minutes at --78, 50 ml. of anacetoxycyclopent-l-cnc. hydrous tetrahydrofuran and 5 ml. of acetic anyhdrid a. Likewise.substituting Z-mcthylcyclopcnt-Z-cnis added. The reaction mixture isthen stirred 20 mi l-one. for cyclopent-Z-en-l-one. and other freshlypreutes at --30C and then allowed to warm to room tempared (dl) alkenylcopper(l) lithium reagents. prepared pcrature for 30 minutes. Theresulting mixture is in Preparation [(6) (a). for (dl) octenyl copper(l)lithpoured into 300 ml. of ice water and extracted twice i r a ent. inthe procedure of Example HA). is prowith 120 ml. ofether. The combinedethereal solutions ductive f h respective .3 3 are washed with 200 ml.of water. dried over sodiumdimethylsiloxy-trans-l-alkcnyl)-2-mclhyl-l-ztcetoxy sulfate andconcentrated in vacuo. The resulting rcsil pp f example. due ischromamgmphed on 8- of silica gel and (dl)-3B-(3a-andBfi-t-butyldimethylsiloxy-trnns-lthose fractions eluted with to ethylacetate in hcxcnyn-zqnclhyl-l-agc[gxycycl0pcnl-I-cnc. hexane yield (dl)-B-( B- y y (dl)-3B-(3a-and3B-t-butyldimethylsiloxy-trans-lsiloxy'tl'ans' l yn l y y l decenyl)-2-methyll -acetoxycyclopent- I -ene. and

a. Similarly. substituting other freshly prepared (dl) (d1).3B.(3-t-butyldimethylsiloxy-trans-lalkenyl copper(l) lithium reagents.prepared in Prcpa- 20 d d ny])-2-methyl l-acetoxycyclopent-l-ene. foroctenyl pp lithium E. Likewise. substituting 2-methylcyclopent-2-en- 8in the Procedurc of Examplc HA) is Producfive l-one. forcyclopcnt-2-cn-l-one. and freshly prepared of respecfivc 54 l y y 3-(S)alkenyl copper (l) lithium reagents. prepared insiloxy-transl-alkenyl)-l-acetoxycyclopent-l-enes. for preparation 1 bfor dl) uctcnyl coppcrfl) lithcxample- 25 ium reagent, in the procedureof Example HA). is pro- B( B" y y ductive of the respective 3a-and3fl-(3a-t-butyldimehsxcnyll-lacetoxyeyclopsnslsns. thylsiloxy-transl-alkenyl )-2-methyll -acetoxyeyclo- (dl)-3B-(3a-and3B-t-butyldimethylsiloxy-trans-l penbpenes' f example yh-loxycy lpcnt-l-cne. and Sa-and 3fl-(Ba-t-butyldimethylsiloxy-transl p-l fiy y 3ooctenyl)-2-methyl-l-acetoxycyclopent-l-enes.

yn"' y 3a-and 3B-(3a-t-butyldimethylsil0xy-trans-hexenyl 8. Similarly.substituting freshly prepared 3-(S) alke-2-mcthyl-l-acctoxycyclopent-l-enes. nyl copper(l) lithium reagents,prepared in Preparation Isa-and 3fi-(3a-t-butyldimethyl5iloxy-trang-dl). 1(0) (b). for (dl) octenyl copper (l) lithium reagent. inZ-methyl-l-acetoxycycl0pent-l-enes. and the procedure of Example l(A).is productive of the 35 Ba-and3B-(3a-t-butyldimethylsiloxy-transrespective 3G-8lld 3B-(3a-t-butyldimethylsiloxy-transdodecenyl)-2-methyll -acet0xycycl0pcntl-enes. yl-l-a t y y p ntfor mpl F. Likewise. substitutingZ-methylcyclopcnt-Z-en- 30l-8nd 3B-(3a-ty i et ylsiloxy-tra -ll-one. forcyclopent-Z-en-l-one. and freshly prepared yn- Y Y W 40 3-(R) alkenylcopper (l) lithium reagents. prepared in 3a-and3B-(3a-t-butyldimethylsiloxy-trans-l-hex- Preparation 1(6) (c), for (dl)octenyl copper(l) lithnyD-l-acetoxyeyclopent-l-enes. ium reagent. in theprocedure for Example HA). is B4 y y y-" productive of the respective3a-and 3B-(3Bt-butyldc nynl -a t0xy y l p n an dimethylsiloxy-transl-alkenyl )-2-methyll -acetoxycy- Zia-and3B-(Sa-t-butyldimethylsiloxy-trans-ll npl for l yhyy i Zia-and 3 343B-t-butyldimethylsiloxy-transl- C. Similarly. substituting freshlyprepared 3-(R) alkeoctenyl)-2-methyll -acetoxycyclopentl -enc nylcopper(l) lithium reagents. prepared in Preparation Lia-and3B-(BB-t-butyldimethylsiloxy-trans-l-hcx- 1(0) (c). for (dl) octenylcopperfl) lithium reagent. in enyl)-2-methyl-l-acetoxycyclopent-l-enes.the procedure of Example HA). is productive of the so Bot-and3B-(3B-t-butyldimethylsiloxy-trans-lrespective Zia-and3/343B-t-butyldimethylsiloxy-transdecenyl)-2-methyl-l-acetoxycyclopent-l-enes.and l-alkenyl)l-aeetoxycyclopent-l-enes. for example. 3a-and3B-(3fl-t-butyldimethylsiloxy-trans-l- Sa-and3fl-(BB-t-butyldimethylsiloxy-transl dodecenyl)-2-methyll-acetoxycyclopentl -enes.

octenyl l -acetoxycyclopentl -enes. Sui-and3B-(SB-t-butyldimethylsiloxy-trans-l-hex- EXAMPLE 2enyl)-l-acetoxycyclopent-l-enes. Step (b) la A CH ca (CH CH osilca C(CHosi(cn c(cn 3 Ba-and 3;3-( JB-t-butyldimethylsiloxy-transl whereindcceny|)-l-acetoxycyclopent-l-enes. and is Sol-and 3B-(3B-t-butyldimethylsiloxy-transl A is -ca ten co R2 s 2 wa -J- (H co Ror:

in which in A" and A, R is alkyl of from one through ten carbon atoms;

n is a whole integer from zero through four; and

p is a whole integer from one through six; and

Ac, R. m and the wavy line( I are defined as in Example l.

A. O.l90 g. of lithium is dissolved in I20 ml. of anhydrous ammonia andthe resulting blue solution cooled to 78C., and a solution of 3.66 g. of(dl)-3fl-(3aand 3 B-t-butyldimethylsiloxy-transl -octenyl i-acetoxycyclopent-l-ene. prepared in Example NA). in 30 mi. oftetrahydrofuran is added over a five minute period. After another fiveminutes, 3 ml. of trimethyiborate in 4 ml. of tetrahydrofuran is addedand the solution warmed to -5 SC for minutes. A solution of 10 g. ofmethyl 3-(5-chloromethylfur-2-yl)propanoate, prepared in Preparation2(0), in 10 ml. of tetrahydroturan is added over three minutes and thereaction allowed to stir at --55C. for 30 minutes. 3 O. of ammoniumchloride is added and the ammonia removed by a stream of nitrogen at atemperature below -l5C. The thus produeted residue is poured into 500 g.of ice. 200 ml. of ether and 50 ml. ofaeetic acid. The ethereal layer isseparated and the aqueous layer washed with another 200 ml. portion ofether. The combined ethereal solutions are washed with saturated sodiumchloride. dried over sodium sulfate and concentrated in vacuo to yield(dl)-2a-[(2.2'-earbomethoxyethylfur-5-yi)methyl1-33 -(3a-and3B-t-butyldimethylsiioxy-trans-l-oetenyl)- cyclopentan-l-one.

a. Similarly, substituting other (di)-3p-(3a-andSfl-tbutyldimethylsiloxy-transi -aikenyl l -aeetoxycyclopent-l-enes,prepared in Example l(A) (a), for exampie (dl )-3p-( 3pand3p-t-butyldimethylsiloxy-transl hexenyl)-l-acetoxycyelopent-l-ene,

(dl)-3B-(3aandBfl-t-butyldimethylsiloxy-trans-ldecenyl)-l-acetoxycyelopent-l-ene, and

(dl)-3B-(3aandSB-t-butyldimethylsiloxy-trans-ldodeeenyl)-l-acetoxyeyclopent-l-ene. for(dl)-3B-(3aandSfl-t-butyldimethylsiloxy-trans-loctcnyU-l-aeetoxycyeiopent-l-ene. inthe procedure of Example 2(A), is productive oi the respective (dl)-2a-[(2,2-earbomethoxyethylfur-S-yl)methyll-Jfi-(Saand3/94-butyldimethylsiloxy-trans-i-alitenyl)-cyelopentan-l-ones, forexample.

38-(301- and3B-t-butyldimethylsiloxy-trans-l-hexenyl)-cyclopentan-l-one,

3B-(3aand 3B-t-butyldimethylsiloxy-trans-ldecenyl)-cyelopentan-l-one,and

(dl)-2a-[(2,2'-carbomethoxyethylfur-S-yl)methyl]- 3(3-(301- andfifl-t-hutyldimethylsiloxy-trans-ldodecenyl )-cyclopentani -one.

b. Similarly, substituting the 3aand3fl-(3a-t-butyldimethylsiloxy-trans-l-alkenyli-l-acetoxycyclopentl-enes,prepared in Example 1(8). for example.

Baand 3,8--(3a-tbutyldimethylsiloxy-truns-loctcnyl)- l-acet0xycyelopcntl -cne.

3c:- and3,8-(Sa-t-butyldimethylsiloxy-trans-l-hexenyl)-i-aectoxycyclopent-l-ene.

3aand3/3(Ser-t-butyldimethylsiloxy-trans-ldecenyl)-l-aeetoxycyclopent-l-ene.and

3aand3B-(Bert-butyldimethylsiloxy-trans-ldodecenyl)-l-acetoxycyclopent-l-ene,for (dl)-3B-(3aandIiB-t-bulyldimethyisiloxy-truns-loctenyl)-l-acetoxyeyclopent-l-enc. inthe procedure of Example 2(A). is productive of the respective 2a-[(2,2-carbomethoxyethylfur-S-yl)methyll-3B-(3a-tbutyldimethylsiloxy-trunsi-alkenyl)-eyclopentanl-ones and2[3-[(2,2'-carbomethoxyethylfur-5-yl)methyl]-3a-(3a-t-butyldimethylsiloxy-trans-l-alkenyl)-eyclopentan-l-ones, for example,

Za-i(2,2'-carbomethoxyethylfur-5-yl)methylidli-(3a-t-butyldimethysiloxy-trans-l-octenyltcyclopentan-l-one.2a-[(2,2'-curbomethoxyethylfur-5-yl)methyl1-38-(3a-t-butyldimethylsiloxy-trans-l-hexenyl)-cyclopentan-l-one,2a-[(2,2-carbomethoxyethyltur-S-yl)methyl1-3/3(3a-t-butyldimethylsiloxy-trans-l-decenyl)-cyclopentani -one.2ol-[(2,2'-carbomethoxyethylfur-5-yl)methyl1-38-(3a-t-butyldimethyisiloxy-trans-l-dodecenyl)- cyclopentan-l-one,2B-[(2,2'-carbomethoxyethylfur-S-yl)methyl]-3a-(3a-t-butyldimethylsiloxy-trans-l -octenyl )-cyclopentan-l-one.

ZB-l(2,2-carbomethoxyethylfur-5-yl)methyll-Ba-(3a-t-butyidimethylsiloxy-transl -hexcnyl )-cyclopentan-l-one,Zfl-i(2.2'-carbomethoxyethylfur-5-yl)methyl1-301-(3a-t-butyldimethylsiloxy-transl -decenyl )-cyclopentan-l -one, and

2B-[(2,2'-carbomethoxyethylfur-5-yl)methyl1-301-(3a-t-butyldimethylsiloxy-trans-l-dodecenyl)- cyeopentan-l-one. c.Similarly, substituting the 301- and3fi-(3E-t-butyldimethyisiloxy-trans-l-alkenyl)-l-acetoxycyclopent-l-enes. prepared in Example l(C). for example.

3aand 3fl-(3a-t-butyldimethylsiloxy-trans-loctenyl l -acetoxycyclopentl-ene,

30:- and3B-(3a-t-butyldimethylsiloxy-trans-l-hexenyl)-l-acetoxycyclopent-l-ene.

3aand3B-(Zia-t-butyldimethylsiloxy-trans-ldecenyi)-i-acetoxycyclopent-l-ene.and

301- and dodeeonyi)-l-ucctoxycycl0pent-l-ene. for (dl)-3B-(3a and3l:i-t-butyldimcthylsiloxy-truns-loctenyl)-l-acetoxycyclopent-bane. inthe procedure of Example 2(A). is productive of the respective 2a-[(2,2'-carbomethoxyethylfur-5-yl)methyl]-3fl-(3/34-butyldimethylsiloxy-transl 'alkenylh l -acetoxycyclo-3B-(Sa-t-butyldimcthylsiloxy-trans-l- I

1. THE (DL) MIXTURES, D-ISOMERS, AND 3-ISOMERS OF THE COMPOUNDS OF THEFORMULAS
 2. The compounds of Formula (I) of claim
 1. 3. The (dl) mixtureof claim 2 wherein R and R1 are both -H, n is two and m is four, (dl)-2Alpha -((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha - and 3Beta -hydroxy-trans-1-octenyl)-cyclopentan-1-one, and thepharmaceutically acceptable salts thereof.
 4. The compound of claim 2wherein R and R1 are both -H, n is two, the side chain attached at theC-2 carbon atom of the cyclopentane ring is Alpha and the side chainattached at the C-3 carbon of the cyclopentane ring is 3 Beta -(3 Alpha-hydroxy-trans-1-octenyl), 2 Alpha-((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha-hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceuticallyacceptable salts thereof.
 5. The compound of claim 2 wherein R and R1are both -H, n is two, the side chain attached at the C-2 carbon atom ofthe cyclopentane ring is Beta and the side chain attached at the C-3carbon atom of the cyclopentane ring is 3 Alpha -(3 Alpha-hydroxy-trans-1-octenyl), 2 Beta-((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Alpha-hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceuticallyacceptable salts thereof.
 6. The compound of claim 2 wherein R and R1are both -H, n is two, the side chain attached at the C-2 carbon atom ofthe cyclopentane ring is Alpha and the side chain attached at the C-3carbon atom of the cyclopentane ring is 3 Beta -(3 Beta-hydroxy-trans-1-octenyl), 2 Alpha-((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Beta-hydroXy-trans-1-octenyl)-cyclopentan-1-one, and the pharmaceuticallyacceptable salts thereof.
 7. The compound of claim 2 wherein R and R1are both -H, n is two, the side chain attached at the C-2 carbon atom ofthe cyclopentane ring is Beta and the side chain attached at the C-3carbon atom of the cyclopentane ring is 3 Alpha -(3 Beta-hydroxy-trans-1-octenyl), 2 Beta-((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1-one, and the pharmceuticallyacceptable salts thereof.
 8. The compounds of Formula (II) of claim 1.9. The (dl) mixture of claim 8 wherein R and R1 are both -H, n is two, mis four and the hydroxyl group at the C-1 carbon atom of thecyclopentane ring is Alpha , (dl)-2 Alpha-((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta (3 Alpha - and 3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and thepharmaceutically acceptable salts thereof.
 10. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Alpha , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Alpha and the sidechain attached at the C-3 carbon of the cyclopentane ring is 3 Beta -(3Alpha -hydroxy-trans-1-octenyl), 2 Alpha-((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha-hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and thepharmaceutically acceptable salts thereof.
 11. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Alpha , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Beta and the sidechain attached at the C-3 carbon atom of the cyclopentane ring is 3Alpha -(3 Alpha -hydroxy-trans-1-octenyl), 2 Beta-((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Alpha-hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and thepharmaceutically acceptable salts thereof.
 12. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Alpha , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Alpha and the sidechain attached at the C-3 carbon atom of the cyclopentane ring is 3 Beta-(3 Beta -hydroxy-trans-1-octenyl), 2 Alpha-((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and thepharmaceutically acceptable salts thereof.
 13. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Alpha , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Beta and the sidechain attached at the C-3 carbon atom of the cyclopentane ring is 3Alpha -(3 Beta -hydroxy-trans-1-octenyl), 2 Beta-((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and thepharmaceutically acceptable salts thereof.
 14. The compound of claim 8wherein R and R1 are both -H, q is two, p is three, the hydroxyl groupat the C-1 carbon atom of the cyclopentane ring is Alpha , the sidechain attached at the C-2 carbon atom of the cyclopentane ring is Betaand the side chain attached at the C-3 carbon atom of the cyclopentanering is 3 Alpha -(3 Beta -hydroxy-trans-1-octenyl), 2 Beta-(5-carboxy-2,2-dioxido-2-tHiapent-1-yl)-3 Alpha -(3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1 Alpha -ol, and thepharmaceutically acceptable salts thereof.
 15. The (dl) mixture of claim8 wherein R and R1 are both -H, n is two m is four, and the hydroxylgroup at the C-1 carbon atom of the cyclopentane ring is Beta , (dl)-2Alpha ((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha - and 3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and thepharmaceutically acceptable salts thereof.
 16. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Beta , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Alpha and the sidechain attached at the C-3 carbon of the cyclopentane ring is 3 Beta -(3Alpha -hydroxy-trans-1-octenyl), 2 Alpha((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Alpha-hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and thepharmaceutically acceptable salts thereof.
 17. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Beta , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Beta and the sidechain attached at the C-3 carbon atom of the cyclopentane ring is 3Alpha -(3 Alpha -hydroxy-trans-1-octenyl), 2 Beta-((2,2''-carboxyethylfur-5-yl)methyl)-3 Alpha -(3 Alpha-hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and thepharmaceutically acceptable salts thereof.
 18. The compound of claim 8wherein R and R1 are both -H, n is two, the hydroxyl group at the C-1carbon atom of the cyclopentane ring is Beta , the side chain attachedat the C-2 carbon atom of the cyclopentane ring is Alpha and the sidechain attached at the C-3 carbon atom of the cyclopentane ring is 3 Beta-(3 Beta -hydroxy-trans-1-octenyl), 2 Alpha-((2,2''-carboxyethylfur-5-yl)methyl)-3 Beta -(3 Beta-hydroxy-trans-1-octenyl)-cyclopentan-1 Beta -ol, and thepharmaceutically acceptable salts thereof.
 19. The compounds of theFormula (I) of claim 1 wherein R is -CH3.
 20. The compounds of Formula(II) of claim 1 wherein R is -CH3.
 21. Process for the production of acompound selected from the (dl) mixtures, d-isomers and l-isomers of thecompounds of the formulas